There are a variety of conditions which result in pathologic chronic collection of bodily fluids within the body of a person or where the removal of certain bodily fluids may be desirable. In particular, it may be desirable to remove cerebrospinal fluid (CSF) from certain patients with Alzheimer's disease, thereby eliminating or reducing the concentration of certain particles, such as beta amyloid (BA) and tau.
The brain and spinal cord are encased within the cranium and vertebral column inside a thin membrane known as the arachnoid. The volume of the intracranial space is on average about 1700 mL. The volume of the brain is approximately 1400 mL; the volume of the intracranial blood is approximately 150 ml; the remaining 150 mL is filled with CSF. The CSF circulates within the subarachnoid space. It is formed principally by the choroid plexuses, which secrete about 80% of the total volume. The sources of the remainder are the vasculature of the subependymal regions, and the pia mater. The total volume of the CSF is renewed several times per day, so that about 500 mL are produced every 24 hours.
The CSF is absorbed through the arachnoid villi, located principally over the superior surfaces of the cerebral hemispheres. Some villi also exist at the base of the brain and along the roots of the spinal nerves. The absorptive processes include bulk transport of large molecules and diffusion across porous membranes of small molecules. See, e.g., Adams et al., (1989) “Principles of Neurology,” pp. 501-502.
The principle on which this invention is based is that in some persons with Alzheimer's disease there is dysfunction of the CSF resorptive mechanism, leading to the retention in the CSF of substances which result in histologic lesions associated with adult-onset dementia of the Alzheimer's type, or which are neurotoxic, or both.
There are several examples of low-molecular weight proteins or peptides that are known to be present in elevated concentrations in the CSF of persons suffering from adult-onset dementia of the Alzheimer's type. For example, elevated levels of BA have been found in the CSF of patients with early-onset Alzheimer's disease. See, Nakamura et al., (1994) “Amyloid beta protein levels in cerebrospinal fluid are elevated in early-onset Alzheimer's disease,” Ann. Neurology 36: 903-911. BA is known to self-aggregate into molecules of amyloid of the type that typify the core plaques found in the brain in persons suffering from adult-onset dementia of the Alzheimer's type. In fact, BA deposition in the brain is the only microscopic lesion specific for Alzheimer's disease. Furthermore, BA has been shown to be neurotoxic, as described in Bush et al., (1992) “Beta A-4 amyloid protein and its precursor in Alzheimer's disease,” Pharmac. Tera. 56: 97-117. BA is also a component of microscopic cerebral lesions known as neurofibrillary tangles, characteristically found in adult-onset dementia of the Alzheimer's type.
Beta-2 microglobulin is another example of a low-molecular-weight protein whose concentration in the CSF increases with age and reaches high levels in patients with adult-onset dementia of the Alzheimer's type, as reported in Martinez et al., (1993) “Relationship of interleukin-1 beta and beta.sub.2-microglobulin with neuropeptides in cerebrospinal fluid of patients with dementia of the Alzheimer type,” J. Neuroimmunology 48: 235-240. Beta-2 microglobulin is associated with amyloid deposits in some tissues of patients on long-term renal hemodialysis. See, Ono et al., (1994) “Formation of amyloid-like substance from beta-2-microglobulin in vitro. Role of serum amyloid P component: a preliminary study,” Nephron 66: 404-407.
Another substance that accumulates in the CSF in patients with adult-onset dementia of the Alzheimer's type is tau, a component of the neurofibrillary tangles found in involved brain tissue. Tau concentrations in CSF are regularly increased in this syndrome with eight fold increases present in half of the patients, as reported in Arai et al., (1995) “Tau in cerebrospinal fluid: a potential diagnostic marker,” Ann. Neurology 38: 649-52.
Researchers have also discovered that oligomeric assemblies of beta amyloid peptides of 42 amino acids (Aβ42) are the probable source of cellular toxicity in human brains. Aβ42 is a major constituent of plaque and vessel amyloid in Alzheimer's disease. Aβ42 has been suggested to promote tau phosphorylation and toxicity in Alzheimer's disease pathogenesis. The dimer, trimer, and tetramer forms of oligomers, which have molecular weights from 4 to 60 kDa, are probably the most toxic oligomers. Therefore, it is desirable to remove these particular particles from the CSF.
Previously-known devices have attempted to use filtration techniques to remove or reduce concentrations of harmful proteins from patient body fluids. For example, Matkovich, U.S. Pat. No. 5,334,315 describes a method and device that can be used to remove a body fluid from a patient, treat that fluid to remove an undesirable component, and return the fluid to the patient. That patent includes a partial list of the types of deleterious or undesirable substances that may be removed from a fluid, such as proteins, polypeptides, interleukins, immunoglobulins, proteases and interferon. The fluids from which these substances may be removed are described as including CSF, blood, urine and saliva. However, Matkovich does not suggest that his method and device could be used to treat patients suffering from adult-onset dementia of the Alzheimer's type.
Kirsch et al., U.S. Pat. No. 5,385,541 describes a CSF shunt mechanism used to treat hydrocephalus by draining CSF into the patient's abdomen, chest or vascular system. The system may include a one-way valve to prevent backflow. Kirsh does not describe the use of such a system to treat adult-onset dementia of the Alzheimer's type, however. Likewise, Ruzicka et al., U.S. Pat. No. 4,950,232 discloses another CSF shunt system, but again does not suggest the possible applicability of using such a shunt to treat adult-onset dementia of the Alzheimer's type.
Chen et al., (1994) “Effectiveness of Shunting in patients with normal pressure hydrocephalus predicted by temporary, controlled-resistance, continuous lumbar drainage: a pilot study,” J. Neurol. Neurosurg. Psychiatry 51:1430-1432, describes use of a “silicon” catheter for draining CSF from the subarachnoid region into an external collection bag.
It has been theorized that the removal of the proteins BA and tau from the CSF in the brain may slow the advance of Alzheimer's disease. Previous attempts to use a standard shunt, like a hydrocephalus shunt, to move CSF from the brain to the abdomen have failed since the deleterious proteins were believed to have found their way back to the brain. Other attempts to remove proteins within the CSF include drugs, which result in undesirable side effects.
It would be desirable to provide methods and apparatus to reduce the concentration of proteins BA and tau within the CSF in the brain.
More specifically, it would be desirable to provide methods and apparatus to remove the harmful particles from the CSF in the brain and prevent the particles from moving or migrating back into the brain.
As described above, the total volume of CSF is renewed several times per day. The continual turnover of CSF is considered to play a key role in the clearance of toxic particles, such as BA and tau. CSF turnover is directly proportional to CSF formation rate and inversely related to the volume of the CSF space.
It is believed that in some persons with Alzheimer's disease, there is a trend towards lower CSF production, hence a decrease in CSF turnover, and greater resistance to CSF outflow. See, Silverberg et al., (2003) “Alzheimer's disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis,” Lancet Neurol 2(8):506-511.
Therefore, it further would be desirable to provide methods and apparatus to replenish the volume of CSF in the cerebral ventricle after the removal of CSF to enhance CSF turnover and reduce BA and tau concentrations in the brain.